INTRODUCTION: Medication-Related Osteonecrosis of the Jaw (MRONJ) is a condition marked by osteonecrosis of the jaw bone and other symptoms seen following invasive surgical procedures in patients administered bone-modifying agents. Once disease develops, a patient's ADL levels are significantly compromised. However, the pathogenesis of this disease is not clearly understood. Bisphosphonates (BPs) are bone resorption inhibitors commonly used to treat osteoporosis. Although not confirmed, it is generally believed that MRONJ risk is higher in the presence of injectable rather than oral formulations. Here, we assessed risk of developing ONJ in mice in the presence of 3 different BPs-zoledronate, ibandronate, or alendronate-that are administered clinically intravenously or via infusion. MATERIALS AND METHODS: Eight-week-old wild-type mice were administered zoledronate, alendronate, ibandronate or PBS vehicle subcutaneously once a week for 2 weeks. Then the right first molars in the mandible were extracted. Six-weeks later, osteonecrosis development was analyzed by histochemistry. RESULTS: Among mice administered BPs, mice treated with zoledronate exhibited the highest frequency of osteocytes exhibiting osteonecrosis. Bone mineral density was higher in mice receiving zoledronate, alendronate, or ibandronate than in PBS control mice, but effects of the 3 drugs were comparable. Moreover, formation of multi-nuclear osteoclasts in vitro was most strongly inhibited by zoledronate, followed by alendronate and ibandronate. CONCLUSION: Administration of BPs with high osteoclastogenesis inhibitory potential, such as zoledronate, increases risk of ONJ development after tooth extraction more than treatment with other agents tested, even at equivalent dosage.